ORALLY ACTIVE AND SELECTIVE ENKEPHALIN PSEUDOPEPTIDES

口服活性和选择性脑啡肽假肽

• 批准号: 3210212
• 负责人: ARNO F SPATOLA
• 金额: $ 7.89万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1990-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3210212
• 关键词: amides; blood brain barrier; chemical structure function; conformation; cyclic compound; drug design /synthesis /production; dynorphins; enkephalins; neuropeptide receptor; opiate alkaloid; oxidation reduction reaction; peptides

Recent findings from this lab and others have demonstrated that backbone modifications render peptides more stable toward enzymatic degradation and often results in increased potency. For example a cyclic pentapeptide containing the psi (CH2S) amide replacement was nearly 10 times more potent than its amide parent in the mu selective guinea pig ileum assay. Most current effort is being directed as finding Mu, delta, or Kappa- selective analogs which regain oral activity. Yet our psi (CH2S) analogs proved to have potency toward both mu and delta receptors and, so far, oral activity has not been demonstrated. Since the specific modification sites and type are so critical to the resulting physical properties of the modified peptides, we propose an expanded study of enkephalin-related cyclic pseudopeptides based on such potent parents as the DiMair- Schiller mu-selective agonist, and the Hruby-Mosberg delta- selective DPDPE. Introduction of psi (CH2S) modifications directly by solid phase synthesis as well as preparation of more polar psi (CH2SO) and psi (CH2SO2) derivatives to probe the Schwyzer hypothesis are also among the objectives of the proposed study. By systemically exploring the changes caused by the peptide backbone modifications on enzymatic stability, transport, selectivity, conformation, and biological activity, it should be possible to design analogs that retain selectivity while processing enhanced metabolic stability and oral activity. In addition hybrid structures between cyclic enkephalins and the kappa-selective dynorphin derivatives will be prepared to test various models of receptor occupancy and selectivity.

该实验室和其他实验室的最新发现表明， 主链修饰使肽对 酶降解，并且经常导致效力增加。 例如，含有psi（CH 2S）的环状五肽 酰胺替代物的效力几乎是其10倍 酰胺母体在mu选择性豚鼠回肠试验中的作用。 最 目前的工作是寻找Mu，Delta或Kappa- 选择性类似物，恢复口腔活性。 然而，我们的psi（CH 2S） 类似物被证明对μ和δ都有效力 受体，到目前为止，口服活性尚未得到证实。 由于特定的修饰位点和类型对于 修饰肽的物理性质，我们 建议对脑啡肽相关的周期性 基于诸如DiMair之类的有效亲本的假肽， Schiller μ-选择性激动剂和Hruby-Mosberg delta- 选择性DPDPE。 引入psi（CH 2S）修改 直接通过固相合成以及制备更多 极性psi（CH 2SO）和psi（CH 2SO 2）衍生物，以探测 Schwyzer假说也是 建议的研究。 通过系统地探索 肽骨架修饰对酶稳定性的影响， 运输，选择性，构象和生物活性，它 应该可以设计保留选择性的类似物， 加工增强了代谢稳定性和口服活性。 在 环脑啡肽和环脑啡肽之间的额外杂合结构 将制备κ-选择性强啡肽衍生物， 受体占有率和选择性的各种模型。